Twin studies have been pivotal in demonstrating the importance of gene-environment interplay in the development of many behavioral outcomes. The parent grant of this revision application (Gene-Environment Interplay in Adolescent Alcohol Use) has the goal of specifically delineating these gene-environment processes with respect to alcohol use and related behaviors, using the wealth of social-environmental information collected as part of a longitudinal Finnish twin study, FinnTwin12 (FT12). The FT12 sample provides a unique opportunity to study gene-environment interaction processes, as it is a large, population-based study of ~5500 twins, with extensive phenotypic assessments at ages 12, 14, 17, and 22. In addition, information about environmental risk and protective factors relevant to adolescent substance use across a variety of domains (family, friends, and neighborhoods) has been collected. In the first 2.5 years of the parent grant, we have successfully identified a number of environments that moderate the importance of genetic effects, when modeled latently. For example, we find that genetic influences on substance use are greater in environments characterized by low parental monitoring and higher substance use among friends. However, no specific genes have been measured as part of the parent grant;rather the heritability of the trait, inferred based on differences in the similarity of monozygotic versus dizygotic twins, has been shown to differ as a function of specific environmental factors. With the rapid advances in gene identification efforts over the last several years, the next logical step is to use this information to test whether these environments moderate the effects associated with specific genes. By the proposed start date of this application DNA will be available on >1000 twins. This revision application requests funds for a two year period in order to (Aim 1) genotype a panel of candidate genes that have previously been demonstrated to have main effects on alcohol use and related outcomes, and (Aim 2) conduct analyses testing for moderation of genetic effects by specific environments. Successfully understanding gene-environment interplay will necessitate careful attention to what environmental factors are likely to be relevant, and at what developmental periods. We will use the findings from the twin analyses conducted under the parent grant to guide the selection of environments and outcomes to test hypotheses about the moderation of risk associated with specific genes. The involvement of several of the key personnel on this grant in several of the largest on-going gene identification projects related to substance use, as well as the use of a novel bioinformatics integration program, will ensure selection of a strong set of candidate genes for analysis. By bringing together expertise from investigators with diverse backgrounds across VCU, Indiana University, and the University of Helsinki, and adding genotyping to the FT12 study, this transdisciplinary project has the potential to significantly advance our understanding of how genetic and environmental influences interact to contribute to the development of alcohol use and related outcomes. PUBLIC HEALTH RELEVANCE: Adding a specific genotyping component to this rich phenotypic, longitudinal dataset (FinnTwin12) will provide a cost-effective means to extend our twin analyses of gene-environment interplay to test hypotheses about how the environment moderates the risk associated with specific genes. Understanding how environmental context moderates the risk associated with specific, measured genes will be critical for developing more informed prevention and intervention efforts in the future.